Substituted morpholines are commercially available and widely used as dispersing agents for waxes and the like. These morpholines are easily prepared from substituted diethanolamines by closing the ring.
Substituted morpholin-2-ones ("2-morpholones") on the other hand, are relatively uncommon compounds known to be useful in pharmaceutical preparations, and not easily prepared. Such 2-morpholones are conventionally prepared as described in Heterocyclic Compounds, Vol. 6, by Robert C. Elderfield in the chapter entitled "The Monocyclic Oxazines", John Wiley & Sons, Inc. New York (1957).
More recently a mixture of 2-morpholone dimers was produced by irradiation of 5,6-dihydro-3,5,5-trimethyl-1,4-oxazin-2-one in 2-propanol solvent at -15.degree. C. (see "An Unusually Weak Carbon-Carbon Single Bond" by Koch, T. H., Olesen, J. A., and DeNiro, J. in J. Am. Chem. Soc. 97:25, 7285-80, 1979). The mixed dimers were found to be thermally unstable in solution, and in the presence of oxygen the dimer was rapidly oxidized to 5,6-dihydro-3,5,5-trimethyl-1,4-oxazin-2-one; but prolonged heating in the absence of oxygen gave a mixture of the foregoing oxazine and 3,5,5-trimethylmorpholin-2-one ("morpholone"). The morpholone so formed must, as a result, have only one substituent on the C atom in the "3" position (C.sup.3) of the ring. Though there are two alkyl substituents on the C.sup.5 atom of the ring, it will be realized that the substituents on this C.sup.5 atom are necessarily lower alkyl. Thus the prior art monomer is a tri-substituted morpholone with only a single substituent on the C.sup.3 atom, and it may not be tetra-substituted with alkyl substituents.
Still more recently, a 5,5-dimethyl-3-phenyl-2-morpholone was prepared which was somewhat unstable and existed in equilibrium with a ring-opened product identified as methyl-2-phenyl-2-(1,1-dimethyl-2-hydroxyethyl)aminoacetate (see "Electron-Transfer Chemistry of the Merostabilized 3,5,5-Trimethyl-2-morpholinon-3-yl Radical" by Burns, J. M., Wharry, D. L. and Koch, T. H., J. Am. Chem. Soc., 103, 849-856, 1981), but note that the 3-position cannot be disubstituted.
Research probing the reactions of the dimers resulted in the knowledge that a mixture of meso and dl dimers heated with 2,2'-azobis(2-methylpropionitrile) produced [2'-(2'-cyanopropyl)]-3,5,5-trimethylmorpholin-2-one. This cyanoalkyl substituted-trimethylmorpholone and the phenyl-substituted-trimethylmorpholone are the only tetra-substituted 2-morpholones known. The substituents on the N-adjacent C atoms cannot be changed because of the recognized relative instability of the lactone ring. For example, it has been found that this ring can neither be reduced nor oxidized without opening it. Thus, I know neither of any tri- or tetra-substituted morpholines which may be derived from known 2-morpholones, nor of any 2-morpholones which can be derived by replacement of the cyanoalkyl or phenyl substituents on the C.sup.3 atom by another substituent without disrupting the lactone ring. Nor do I know of any method for preparing a C.sup.3 -cyanoalkyl-substituted-2-morpholone or C.sup.3 -phenyl-substituted-2-morpholone, with other than lower alkyl substituents on the C.sup.5 atom of the lactone ring.
Stated differently, it was not heretofore known how polysubstituted compounds may be prepared which have either (a) three substituents which are not lower alkyl, or, (b) three substituents, one of which on C.sup.3 is phenyl or cyanoalkyl, and at least one of the remaining two substituents on the other N-adjacent C atom is not alkyl, or, (c) four substituents all of which may be alkyl, on the (combined) N-adjacent C atoms. The term "polysubstituted" is specifically used in this specification to connote that in the claimed compounds of this invention, a total of three or more substituents is necessarily present on the two N-adjacent C atoms, combined; and, two substituents, which may be cyclized, are always present on the C.sup.3 atom when the compound is a 2-morpholone. In this sense, it will be recognized that if each of the substituents on the one N-adjacent C atom are cyclic substituents, and the substituents on the other N-adjacent C atom are not, then there are a total of four substituents; there are also four substituents if the two substituents on each N-adjacent C atom are together cyclized.
The problem with preparing polysubstituted 2-morpholones carries over to the preparation of polysubstituted morpholines. For example, it is known that reductive alkylation of HOCH.sub.2 C(CH.sub.3).sub.2 NH.sub.2 with CH.sub.3 COCH.sub.2 OH yields [(HOCH.sub.2 C(CH.sub.3).sub.2 ]NH[CH(CH.sub.3)CH.sub.2 OH] which upon cyclization by heating with conc H.sub.2 SO.sub.4 produces 3,5,5-trimethylmorpholine (see 112872h Chem. Abstr. Vol 71, pg 374, 1979), but this approach cannot produce a trimethyl-2-morpholone.
The key to providing three or more substituents on the combined N-adjacent C atoms, is to provide the polysubstituents on the C atoms before the ring is closed. Only a few such polysubstituted compounds are known. In these known compounds, only specific substituents may be present because of the manner in which the compounds are necessarily prepared. Such compounds are 3-[2'-(2'-cyanopropyl)]-3,5,5-trimethylmorpholin-2-one, prepared as described in the Koch et al. articles, supra; and, 5,5-dimethyl-3-phenyl-2-morpholinone, prepared as described in the Burns et al article, supra. Though sodium hydroxyethylaminoacetate is easily prepared, and two substituents may be made on one or the other N-adjacent C atom, or, one substituent may be made on one and also (one) on the other N-adjacent C atom, polysubstituted hydroxyethylaminoacetates ("HEAA" for brevity) having three or more substituents have not been known or made because of the steric hindrance problems, inter alia. Further, though polysubstituted aminodiols such as [HOCH.sub.2 C(CH.sub.3).sub.2 ]NH[CH(CH.sub.3)CH.sub.2 OH] are known, I know of no apparently operable method for converting such aminodiols to N-hydroxyalkylamino acids. As a result, tri-substituted or tetra-substituted N-adjacent C atoms of an alkali metal hydroxyethylaminoacetate are not known.
Hindered amines, to which general class the compounds of this invention belong, are known to have utility as u-v light stabilizers in synthetic resins subject to actinic radiation. However, not all hindered amines are effective stabilizers against u-v light degradation in normally solid polymers. Some hindered amines are thermally unstable at as low as 100.degree. C. which precludes their use in any organic material which is processed at or above that temperature. Further, particularly with polysubstituted heterocyclic ring compounds, N atoms in the ring are known to have a beneficial effect but there is no more reason to expect that a polysubstituted morpholone might be effective than there is to believe that a polysubstituted thiomorpholine might be effective. More particularly, it was known that dimers of 5,6-dihydro-3,5,5-trimethyl-1,4-oxazin-2-one are photoreductive and thermally unstable in solution when heated to 80.degree. C., and that in solution, these dimers exist in equilibrium with a radical at room temperature (Koch et al, supra). Therefore, it was quite surprising that a polysubstituted 2-morpholone or a polysubstituted related compound, would provide excellent u-v light stability.
Because of the unpredictability of the effectiveness of various hindered amines solely based on their (hindered) structure, much effort has been expended to synthesize hindered amines which must then be tested for possible utility as u-v light stabilizers. One of the synthesis is described in an article titled "Hindered Amines. Novel Synthesis of 1,3,3,5,5-Pentasubstituted 2-Piperazinones" by John T. Lai in J. Org. Chem. 45, 754 (1980). The concept of retaining the "2-keto" ring structure of a heterocyclic ring containing at least one N atom was the basis upon which the search for effective 2-morpholones was initiated. The necessity of providing more than two substituents on the N-adjacent C atoms spurred the discovery of the application of a "ketoform synthesis" to solve the problem. This invention derives from further research in the field of the synthesis of hindered amines, and an evaluation of their effectiveness as u-v light stabilizers.
Hindered amines of the prior art are generally complex compounds not prepared with notable ease, and their properties, particularly their compatability in various synthetic resins, is difficult to predict. Apparently small differences in structure, result in large differences in performance. Prolonged efforts to provide simpler compounds which are relatively easily prepared, have resulted in the 2-keto-1,4-diazacycloalkanes and the 2-keto-1,5-diazacycloalkanes disclosed in U.S. Pat. Nos. 4,190,571 and 4,207,228.
The present invention is particularly directed to (a) novel polysubstituted alkali metal hydroxyethylaminoacetates, (b) a novel synthesis for a polysubstituted alkali metal hydroxyethylaminoacetate, (c) novel compositions in which a polysubstituted alkali metal hydroxyethylaminoacetate is incorporated, (d) novel polysubstituted 2-morpholones, (e) a novel synthesis for polysubstituted 2-morpholones, (f) novel compositions stabilized against u-v light degradation by the presence of a stabilizing amount of the 2-morpholones, (g) novel polysubstituted aminodiols, (h) novel compositions stabilized against u-v light degradation by the presence of a small but effective amount of a polysubstituted aminodiol, (i) novel polysubstituted monoaza crown ethers, (j) synthesis of polysubstituted monoaza crown ethers, (k) novel compositions stabilized against u-v light degradation by the presence of an effective amount a polysubstituted monoaza crown ether, (l) polysubstituted morpholine, (m) synthesis of polysubstituted morpholine by cyclization of an aminodiol with an alkanesulfonic acid, (n) novel compositions stabilized against u-v light degradation by the presence therein of an effective amount of a polysubstituted morpholine, (o) novel polysubstituted aminodiethers, and (p) novel compositions stabilized by the presence therein of an effective amount of a polysubstituted aminodiether.
The synthesis of the novel stabilizers of this invention is facilitated by the peculiar action of certain onium salts in an aqueous alkaline medium, which action facilitates the interaction of an amine nucleophilic agent such as a primary or secondary amine, with chloroform or other trichloromethide generating agent, and a ketone or aldehyde. The organic onium salts of nitrogen, and phosphorus are well known. They are ionized in aqueous solutions to form stable cations. Certain onium salts have provided the basis for phase transfer catalysis in a wide variety of reactions, a recent and comprehensive review of which is contained in Angewandte Chemie, International Edition in English, 16 493-558 (August 1977). Discussed therein are various anion transfer reactions where the onium salt exchanges its original anion for other anions in the aqueous phase. These ion pairs can then enter a water immiscible, organic liquid phase, making it possible to carry out chemistry there with the transported anion, including OH.sup.- ions. Many reactions involving water immiscible solutions of various simple organic molecules have been described. Though the use of phase transfer catalysts facilitate the cyclization of an appropriately sterically hindered branched chain amine having proximate primary and secondary amine groups amongst plural amine groups in the chain, the reaction has also been found to proceed, though relatively slowly, by simply using a large excess of the ketone or aromatic aldehyde either of which is the essential carbonyl containing compound which contributes the carbonyl group to the 2-position of the diazacycloalkane ring.
A phase transfer catalyzed reaction known as the "ketoform reaction" is disclosed in U.S. Pat. No. 4,167,512, which proceeds by virtue of a phase transfer catalyzed reaction mechanism in which an amine, a haloform and a carbonyl containing ("carbonyl") compound are separate reactants. This reaction is illustrated in one particular example by the reaction of a N,N'-alkyl substituted ethylene diamine with acetone and chloroform; and, in another example, with o-phenylene diamine reacted with cyclohexanone and chloroform. The reaction product in each example is a 2-keto-1,4-diazacycloalkane.
Though both ketones and aldehydes are taught as being effective reactants in the ketoform reaction, it has now been discovered that only ketones and benzaldehyde are effective in the formation of HEAA. Accordingly, my present invention is a particular adaptation of the ketoform reaction to the preparation of alkali metal HEAA, and several successor compounds derived therefrom, including 2-morpholones, aminodiols, monoaza crown ethers, and morpholines, all of which are polysubstituted, and are collectively referred to herein as "HEAA compounds" for brevity.
Very recently, amino acid mixtures, and their alkali metal salts have been prepared as disclosed in U.S. Pat. No. 4,525,294 to Sartori et al., by reductive condensation or amination. But this reaction requires that there must always be a H atom present on each of the carbon atoms on either side of the N atom in the Sartori structure. As a consequence, as Sartori et al teach, the reductive amination of the ketone results in the H atom on the alpha C atom. There is no known way of substituting this H atom.
Also very recently, U.S. Pat. No. 4,542,234 to Reilly et al discloses that the C atoms on either side of a N atom may each be substituted if one starts with an alpha-halo ester and tosylates it. To make my claimed compound in an analogous manner one would have to tosylate a t-butylamine derivative. More specifically, for example, one would have to react 2-maino-2-methyl-2-propanol with alpha-haloisobutyrate, then tosylate the reaction product. Except that there will be no reaction product to tosylate. The reaction product is not formed because of excessive hindrance. It should be noted, in this regard, that di-isopropylamine is a readily available compound, but di-t-butylamine, which is also known, cannot be made by a reaction analogous to that of Reilly et al. (see "Synthesis of di-t-alkylamines" by E. J. Corey and A. Gross, Tetrahedron Letters Vol 25, pgs 491-494, 1984).
Further in this regard, it is well known that a tertiary alkyl halide undergoes an elimination reaction with any amine. For example, t-butyl chloride reacts with t-butylamine to yield isobutylene. When an attempt is made to react alpha-haloisobutyrate with 2-amino-2-methyl-1-propanol, one gets the elimination reaction which yields the methacrylate, not the product of a condensation reaction. This is consistent with the textbook teaching that tertiary substrates do not give the alkylation reaction at all, but undergo preferential elimination. (see Advanced Organic Chemistry by Jerry March, bottom of pg 365, 3rd Ed., John Wiley & Sons, 1985).
One cannot arrive at the least hindered of secondary amines from a tertiary alkyl halide and an amine. Even when one reacts a tertiary alkyl halide with NCl.sub.3 and AlCl.sub.3, one gets a primary amine, not a secondary amine. (see, March, supra).